Evaluation of deep-learning TSE images in clinical musculoskeletal imaging.

In this study, we compared the fat-saturated (FS) and non-FS turbo spin echo (TSE) magnetic resonance imaging knee sequences reconstructed conventionally (conventional-TSE) against a deep learning-based reconstruction of accelerated TSE (DL-TSE) scans. A total of 232 conventional-TSE and DL-TSE image pairs were acquired for comparison. For each consenting patient, one of the clinically acquired conventional-TSE proton density-weighted sequences in the sagittal or coronal planes (FS and non-FS), or in the axial plane (non-FS), was repeated using a research DL-TSE sequence.

Shunt freedom in slit ventricle syndrome: using paradoxical ventriculomegaly following lumbar shunting to our advantage. Illustrative cases.

Background: The authors present two cases of paradoxical ventriculomegaly after lumboperitoneal (LP) shunting in patients with slit ventricle syndrome (SVS).

Observations: After placement of an LP shunt, both patients rapidly developed radiographic and clinically symptomatic ventricular enlargement. The then generous ventricular corridors allowed both patients to be treated by endoscopic third ventriculostomy (ETV) with concurrent removal of their LP shunt.

Demographic Predictors of Treatment and Complications for Spinal Disorders: Part 2, Lumbar Spine Trauma.

Objective: To study the impact of demographic factors on management of traumatic injury to the lumbar spine and postoperative complication rates.

Methods: Data was obtained from the National Inpatient Sample (NIS) between 2010-2014. International Classification of Diseases, 9th revision, Clinical Modification codes identified patients diagnosed with lumbar fractures or dislocations due to trauma.

Untangling Hydrogen Bond Networks with Ion Mobility Spectrometry and Quantum Chemical Calculations: A Case Study on HXPGG.

Ion mobility spectrometry-mass spectrometry and quantum chemical calculations are used to determine the structures and stabilities of singly protonated XaaProGlyGly peptides: HDPGG, HNPGG, HEPGG, and HQPGG. The IMS distributions are similar, suggesting the peptides adopt closely related structures in the gas phase. Quantum chemical calculations show that all conformers seen in the experimental spectrum correspond to the configuration about the Xaa-Pro peptide bond, significantly different from the behavior seen previously for HGPGG.

Enhancing Periconceptional Health by Targeting Postpartum Mothers at Rural WIC Clinics.

The overall goal of this pilot quality improvement (QI) intervention was to (1) assess the feasibility of making a WIC (Women, Infants, and Children) systems-level change that added measurement of maternal weight and discussion of maternal health habits into each postpartum maternal and offspring visit in rural clinics in Colorado and (2) assess the impacts of the intervention on maternal diet, physical activity, and weight status. A mixed-method evaluation approach was used involving the collection of quantitative data (HeartSmartMoms usage reports, manual WIC chart reviews [to calculate screening rates], pre-/postsurveys, and weight status [body mass index]) and qualitative data (focus groups and project team meeting minutes). It was determined it is feasible to make a short-term systems-level change; however, many barriers were encountered in doing so, and the results were not sustained.

Identifying patterns of obesity risk behavior to improve pediatric primary care.

Purpose: To develop profiles of obesity risk behaviors for children and adolescents.

Design And Methods: Risk assessments were obtained from patients (n = 971) at a school-based health center. Latent class analysis was used to create subgroups based on seven indicators measuring diet, activity, and screen time.

P2-quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3/4a protease inhibitors: discovery of MK-2748 and MK-6325.

With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325.

Discovery of diazepane amide DORAs and 2-SORAs enabled by exploration of isosteric quinazoline replacements.

Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines.

Diastereo- and enantioselective three-component coupling approach to highly substituted pyrrolidines.

The enantioselective synthesis of substituted pyrrolidines through a mild Lewis-acid catalyzed three-component coupling reaction between picolinaldehyde, amino acids, and activated olefins is reported. The reaction uses low catalyst loadings of commercially available chiral diamines and copper triflate proposed to self-assemble in conjunction with the chelating aldehydes, 4-substituted-2-picolinaldehydes or 4-methylthiazole-2-carboxaldehyde, to generate a catalyst complex. A model is provided to explain how this complex directs enantioselectivity.

Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2-P4 linkers.

A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.

Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease.

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.

Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.

Mediastinal goiter presenting with ventricular tachycardia.

Background: We report a rare case of a mediastinal goiter confined to the thoracic inlet and cavity presenting with ventricular tachycardia as the sole clinical manifestation.

Methods And Results: The patient did not have any of the typical features of a mediastinal goiter such as neck swelling, dysphagia, or respiratory difficulty, but instead had spontaneous onset of wide-complex tachycardia requiring emergency treatment. This atypical presentation led to initial misinterpretation of imaging studies and delayed diagnosis of the mediastinal mass.

Comparing the Effectiveness of CDSS on Provider's Behaviors to Implement Obesity Prevention Guidelines.

Obesity is a global epidemic demanding the use of clinical decision support tools to help clinicians in the identification, assessment and management of healthy weight gain in children. Over the last decade, numerous systematic reviews have shown that clinical decision support systems (CDSS) have positively impacted clinician's performance for drug ordering/dosing and preventive care reminders. CDSS that are built into the clinician's workflow at the point of care also have a positive impact on provider's performance.

Antibacterial properties of additives used in injection immunotherapy.

Background: Previous studies have reviewed the safety of preparing and administering allergy injection immunotherapy in a physician's office, and showed no evidence of infectious complications. The current study examines the antimicrobial properties of the common additives used in preparation of multidose immunotherapy vials.

Methods: Vials were prepared with varying concentrations of glycerin (0-25%), phenol (0-0.

Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure.

The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.

Advances in cheminformatics methodologies and infrastructure to support the data mining of large, heterogeneous chemical datasets.

In recent years, there has been an explosion in the availability of publicly accessible chemical information, including chemical structures of small molecules, structure-derived properties and associated biological activities in a variety of assays. These data sources present us with a significant opportunity to develop and apply computational tools to extract and understand the underlying structure-activity relationships. Furthermore, by integrating chemical data sources with biological information (protein structure, gene expression and so on), we can attempt to build up a holistic view of the effects of small molecules in biological systems.

Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.

A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.

Evaluation of technology to identify and assess overweight children and adolescents.

Purpose: The current obesity epidemic has produced a generation of children that may be the first to have a life expectancy shorter than their parents. To address the obesity epidemic, experts have published recommendations for providers. Research suggests the publication of guidelines may not change provider behavior.

A transient cell-based phenotype assay for hepatitis C NS3/4A protease: application to potency determinations of a novel macrocyclic inhibitor against diverse protease sequences isolated from plasma infected with HCV.

The potential of hepatitis C virus (HCV) to develop antiviral resistance renders phenotypic analysis of viral relapse or breakthrough sequences essential to the clinical evaluation of HCV antivirals. This work describes a transient assay in which clinical NS3/4A sequences are co-expressed in Huh-7 cells with a reporter whose activity is an easily quantifiable measure of protease activity. The utility of the assay was demonstrated in potency evaluations of a novel protease inhibitor against panels of NS3/4A sequences spanning genotypes 1-3.

Pulmonary embolism outcome: a prospective evaluation of CT pulmonary angiographic clot burden score and ECG score.

Objective: The purpose of this study was to establish whether a correlation exists between the CT pulmonary angiographic clot burden score, the ECG score at diagnosis, and the 12-month mortality rate among patients diagnosed with pulmonary embolism.

Subjects And Methods: A total of 523 consecutive patients who underwent CT pulmonary angiography for a suspected moderate to high pretest probability of pulmonary embolism were recruited from March 2003 to October 2004. There were 105 patients with positive CT pulmonary angiography examinations.

Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease.

Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.

Web service infrastructure for chemoinformatics.

The vast increase of pertinent information available to drug discovery scientists means that there is a strong demand for tools and techniques for organizing and intelligently mining this information for manageable human consumption. At Indiana University, we have developed an infrastructure of chemoinformatics Web services that simplifies the access to this information and the computational techniques that can be applied to it. In this paper, we describe this infrastructure, give some examples of its use, and then discuss our plans to use it as a platform for chemoinformatics application development in the future.